Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
other: Data Review
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Klimisch criteria not applicable

Data source

Reference
Reference Type:
other: Unpublished Data Evaluation
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Principles of method if other than guideline:
Expert Data Evaluation
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not applicable

Results and discussion

Any other information on results incl. tables

DMG has been tested extensively, either as a substance, or as part of a multi-component substance (DBE, Dibasic Esters, EC No.: 906-170-0), and the available studies are summarized in the REACH dossiers for both DMG and DBE. In addition to the 90-day inhalation study mentioned in the CoRAP justification document (Bamberger, 2000), there are 2 additional 90-day inhalation studies available (Kelly 1987a; Kelly 1987b), all with full pathology on either DMG alone, or on DBE. Also, there is a one-generation reproductive toxicity (Inhalation) assay that was run concurrently, but with additional exposure periods, with the Kelly 1987a study. DBE is comprised of 3 substances: DMG (approximately 59%), DMS (Dimethyl Succinate – approximately 20%), and DMA (Dimethyl Adipate – approximately 21%).

 

In the Bamberger (2000) study, DMG was tested at 3 concentrations (10, 50, and 400 mg/m3) while DMA and DMS were only tested at single, very high concentrations in a 90-day inhalation assay. DMG caused a dose-dependent decrease in luteinizing hormone (LH) concentrations that became statistically different from controls only at the highest concentration (400 mg/m3). In addition, DMG caused a statistically significant decrease in serum testosterone concentrations at 2 concentrations (50 and 400 mg/m3). However, the presence of outlier individual values in the control and 10 mg/m3groups (2 outliers in each group) may have biased the statistical significance of the observed decrease (see attached illustration).

The decreases in testosterone and LH were not accompanied by alterations in organ weights or histopathological changes of the male reproductive organs. Serum concentrations of FSH were unaffected by exposure to DMG up to 400 mg/m3. There were no significant hormone alterations in rats exposed to DMA or DMS. There was a treatment related increase in epididymal sperm counts for DMG, DMS, and DMA. Since there wereno hormonal perturbationsnoted with DMA or DMS, the increase in epididymal sperm counts does not appear to be associated with any changes in hormonal decrements in DMG-exposed rats. The epididymal sperm count increases were thought to be spurious in the absence of any histopathological correlate. Additionally, one might expect adecreasein epididymal sperm counts after noting decreases in testosterone and LH, thus providing further indications that the hormonal perturbations, noted in the Bamberger (2000) study, were of no toxicological significance.

 

There was no serum hormone data from any of the 1987 DBE 90-day inhalation studies. However, full histopathology examinations were conducted and no changes in any reproductive organs were noted, even at an exposure concentration of 1000 mg/m3. Additionally, there is a one-generation reproductive toxicity assay (inhalation) for DBE (Kelly, 1988), which was negative for any reproductive endpoints, including male fertility, even at a concentration of 1000 mg/m3that was overtly toxic to parental animals.

 

If DMG were an endocrine disruptor, serum testosterone and LH induced effects would be expected to be observed in the reproductive system of affected rats. Since there were no DMG-specific adverse effects to the reproductive system seen inanystudy with DMG or DBE, DMG should not be considered a suspected endocrine disruptor. There are no changes that are secondary to hormonal changes that can be associated with DMG in any of the studies presented here or found in the DMG or DBE REACH dossiers.

 

From a weight of the evidence approach, using results from additional sub-chronic studies, as well as from a reproductive toxicity study, DMG should not be regarded as a potential endocrine disruptor. For reasons of animal welfare, further animal testing should not be required.

 

References

Kelly (1987a). 90-Day Inhalation Toxicity Study with Dibasic Esters (DBE). DuPont HLR 194-86.

Kelly (1987b). 90-Day Inhalation Toxicity Study in Rats with Dibasic Esters (DBE) -2. DuPont HLR 312-87.

Kelly (1988). Inhalation Reproduction Study in Rats Exposed to Dibasic Esters (DBE), HLR 76-87.

Bamberger(2000). Dimethyl Glutarate, Dimethyl Succinate, and Dimethyl Adipate: 90-Day Inhalation Toxicity Study in Rats. DuPont-3557.

 

Applicant's summary and conclusion

Conclusions:
DMG should not be regarded as a suspected endocrine disruptor and, for reasons of animal welfare, additional animal testing should not be required. In each of the three separate OECD 413 90-day inhalation studies and in an OECD 415 reproductive toxicity inhalation study, there were no adverse health effects observed that can be correlated to the hormonal changes observed in the Bamberger (2000) study.
Executive summary:

DMG has been tested extensively, either as a substance, or as part of a multi-component substance (DBE, Dibasic Esters, EC No.: 906-170-0). From a weight of the evidence approach, using results from multiple sub-chronic studies, as well as from a reproductive toxicity study, DMG should not be regarded as a potential endocrine disruptor. For reasons of animal welfare, further animal testing should not be required.